Lung cancer is the leading cause of cancer death in the United States. Therefore, more effective methods to prevent and treat lung cancer are urgently needed. Epidemiological and animal studies have demonstrated that vitamin A and its natural and synthetic derivatives, retinoids, are promising agents in preventing the development of lung cancer. However, clinical trials have found no preventative effects of vitamin A against lung cancer development, suggesting that retinoid responses may be impaired in lung cancer cells. The effects of retinoids are mainly mediated by two classes of nuclear receptors, the retinoic acid receptors (RARs) and retinoid X receptors (RXRs), both of which are encoded by three distinct genes, alpha, beta, and gamma. In our previous study, we found that retinoid responses are impaired in a majority of lung cancer cells and that loss of RARbeta is primarily responsible for the defect. In addition, we observed that loss of RARbeta can be attributed to abnormal regulation of a RA responsive element (beta RARE) in the RARbeta promoter, due to low levels of COUP-TF that is required to maintain retinoid sensitivity and/or elevated levels of orphan receptor nur77 which inhibits RXR and COUP-TF activities through heterodimers. The loss of RARbeta could also be attributed to low binding activity of a pEA3 binding site in the RARbeta promoter. Furthermore, we demonstrated that nur77 can induce lung cancer cell apoptosis depending on its stimulus. In the proposed study, we will first study the anti-cancer effects of RARbeta by identifying its specific DNA binding sequences and interacting proteins as well as genes mediating its growth inhibition and apoptosis inducing effects. We will then analyze and clone protein that actively binds to pEA3 site and regulates RARbeta promoter activity. In addition, we will study the mechanism by which COUP-TF sensitizes RAREs and their responsiveness to trans-RA. Finally, we will investigate how phosphorylation of nur77 regulates its DNA binding and heterodimerization specificity and their involvement in determining the effects of nur77 on trans-RA resistance and induction of apoptosis, and identify genes responsible for its apoptosis inducing effects. Results from these studies will contribute to our understanding of the mechanism by which RARbeta exerts its anti-cancer activities and how the activities are lost in lung cancer cells, and may provide means to increase retinoid sensitivity in lung cancer cells, thereby enhancing the anti-cancer efficacy and spectrum of retinoids against this diseases.
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